Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a loss of the neurons that control voluntary movements. Patients lose muscle strength and in the final stages of the disease are unable to move and have difficulty swallowing and breathing. Recent advances have been made in understanding the molecular mechanisms that contribute to ALS. In contrast, little progress has been made in drug discovery - none of over 30 new drugs tested in ALS has been found to be effective, and median survival from diagnosis remains at 2-3 years. The purpose of this project, which is a revision to a recent NIH-supported study, is to add substantially to the number of cases in the search for clues for novel treatments by studying individuals who provided blood samples before ALS to determine if they are different from those who remain healthy. During the past 5 years of this project, we have found that ALS risk was inversely associated with long term intakes of vitamin E and other antioxidants, and positively associated with cigarette smoking. In parallel, preliminary evidence emerged that blood levels of urate, a potent antioxidant, are inversely related to the rate of ALS progression - this is encouraging in view of urate's strong antioxidant properties, its robust inverse associations with both risk and progression of Parkinson disease, and the fact that urate concentrations can be increased by administration of inosine (a urate precursor) or other available drugs. Building on these findings, this revision wil increase power to address the following question: whether plasma levels of urate in apparently healthy individuals contribute to predict their ALS risk. Additionally, we will conduct a discovery study for novel risk markers using a metabolomic approach. The proposed aims of our study stand to identify or substantiate major new links to ALS, with realistic prospects for mechanistic insight and therapeutic impact.